The life-long risk of breast cancer ranges from ~12% in the general population, to over 65% in high-risk women (such as BRCA mutant carriers), emphasizing the need for safe and effective chemoprevention. Currently approved drugs, tamoxifen and raloxifene, prevent only ER-positive (ER+) breast tumors. Thus, the prevention of ER-negative (ER-) cancers remains a major challenge. Rexinoid agonists of RXR nuclear receptors, such as Targretin, prevent both ER+ and ER-cancers in animal chemoprevention models; but they induce severe hyperlipidemia, which limits their use. Using structure-based drug design, we developed a structurally unique group of rexinoids, Class III UAB rexinoids (exemplified by UAB125 andUAB126), with potent chemopreventive efficacy in an ER-mouse model. However, these Class III rexinoids are unique among chemopreventive rexinoids in that they actually lower, rather than elevate, serum lipid levels in treated animals. Moreover, our preliminary data suggest that UAB126 prevents diet-induced obesity and metabolic syndrome, both of which increase the risk of developing breast cancer. Thus, we hypothesize that (1) Class III rexinoids can counteract the tumor-promoting effects of high-fat diet and obesity; and (2) the metabolic actions of these rexinoids may, in part, mediate their chemopreventive activity by directly affecting the metabolic homeostasis of normal and/or (pre)malignant mammary epithelial cells. To address these concepts, chemopreventive activity will be evaluated in an ER-mouse model by assessing rexinoid-induced differences in tumor number, tumor mass, and time to tumor occurrence between animals fed normal or high-fat diet (HFD). These studies will reveal the chemopreventive efficacy of Class III rexinoids in a HFD setting. The molecular mechanisms of rexinoid chemoprevention will be addressed with a three-prong approach: (1) using RNAseq to assess gene expression patterns induced by HFD and/or treatment with Class III rexinoids in distinct tissues (mammary tumors, normal mammary tissue, adipocytes), which will identify potential pathways of rexinoid action; (2) using Isothermal calorimetry to assess rexinoid-induced stabilization of select co-regulator:receptor complexes, which will define specific roles of these rexinoids as agonists/antagonists of distinct RXR heterodimers; and (3) using siRNA screening to identify genes and pathways functionally relevant for the chemopreventive action of Class III rexinoids. Integration of these findings will lay the basis for future studies of the causal links between obesity, metabolic syndrome, and initiation and progression of breast cancer.